title: Epigenetics targeted protein-vorinostat nanomedicine inducing apoptosis in heterogeneous population of primary acute myeloid leukemia cells including refractory and relapsed cases.
abstract: Aberrant epigenetics play a key role in the onset and progression of acute myeloid leukemia (AML). Herein we report in silico modelling based development of a novel, protein-vorinostat nanomedicine exhibiting selective and superior anti-leukemic activity against heterogeneous population of AML patient samples (n=9), including refractory and relapsed cases, and three representative cell lines expressing CD34(+)/CD38(-) stem cell phenotype (KG-1a), promyelocytic phenotype (HL-60) and FLT3-ITD mutation (MV4-11). Nano-vorinostat having ~100nm size exhibited enhanced cellular uptake rendering significantly lower IC50 in AML cell lines and patient samples, and induced enhanced HDAC inhibition, oxidative injury, cell cycle arrest and apoptosis compared to free vorinostat. Most importantly, nanomedicine showed exceptional single-agent activity against the clonogenic proliferative capability of bone marrow derived leukemic progenitors, while remaining non-toxic to healthy bone marrow cells. Collectively, this epigenetics targeted nanomedicine appears to be a promising therapeutic strategy against various French-American-British (FAB) classes of AML.
  
  
  BACKGROUND
  Through the use of a protein-vorinostat agent, exceptional single-agent activity was demonstrated against the clonogenic proliferative capability of bone marrow derived leukemic progenitors, while remaining non-toxic to healthy bone marrow cells. The studied epigenetics targeted nanomedicine approach is a promising therapeutic strategy against various French-American-British classes of acute myeloid leukemia.
authors.affiliation: Amrita Centre for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Centre, Kochi, Kerala, India.
authors.forename: Parwathy
authors.initials: P
authors.lastname: Chandran
authors.affiliation: Amrita Centre for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Centre, Kochi, Kerala, India.
authors.forename: Anu
authors.initials: A
authors.lastname: Kavalakatt
authors.affiliation: Amrita Centre for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Centre, Kochi, Kerala, India.
authors.forename: Giridharan Loghanathan
authors.initials: GL
authors.lastname: Malarvizhi
authors.affiliation: Amrita Centre for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Centre, Kochi, Kerala, India.
authors.forename: Divya Rani Vikraman Nair
authors.initials: DR
authors.lastname: Vasanthakumari
authors.affiliation: Amrita Centre for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Centre, Kochi, Kerala, India.
authors.forename: Archana Payickattu
authors.initials: AP
authors.lastname: Retnakumari
authors.affiliation: Department of Medical Oncology, Amrita Institute of Medical Sciences and Research Centre, Kochi, Kerala, India.
authors.forename: Neeraj
authors.initials: N
authors.lastname: Sidharthan
authors.affiliation: Department of Medical Oncology, Amrita Institute of Medical Sciences and Research Centre, Kochi, Kerala, India.
authors.forename: Keechilat
authors.initials: K
authors.lastname: Pavithran
authors.affiliation: Amrita Centre for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Centre, Kochi, Kerala, India.
authors.forename: Shantikumar
authors.initials: S
authors.lastname: Nair
authors.affiliation: Amrita Centre for Nanosciences and Molecular Medicine, Amrita Institute of Medical Sciences and Research Centre, Kochi, Kerala, India. Electronic address: manzoork@aims.amrita.edu.
authors.forename: Manzoor
authors.initials: M
authors.lastname: Koyakutty
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D003198:Computer Simulation; D044127:Epigenesis, Genetic / Q000187:drug effects*; D018922:HL-60 Cells; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008954:Models, Biological; D050997:Nanomedicine / Q000379:methods*; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat
keywords: Acute myeloid leukemia; Epigenetics; Nano-vorinostat; Protein nanomedicine